Summary of Lecture II

7-Oxidation involving carbon-heteroatom systems:

• Nitrogen, oxygen & sulfer.
• Two types of biotransformation reaction
  1-Hydroxylation of the α-carbon atom attached directly to the heteroatom (N, O, S) giving an unstable intermediate which decomposes leading to the break of the carbon-heteroatom bond thus causing Oxidative N-, O-, and S-dealkylation and oxidative deamination.

The presence of a- hydrogen is a must

2-Hydroxylation or oxidation of the heteroatom (N, S only) → N-hydroxylation, N-oxide formation, sulfoxidation and sulphone formation.

a-Oxidation involving carbon–nitrogen systems
1-Oxidation of tertiary aliphatic and alicyclic amines:

• Two types of oxidation reactions.
• Catalyzed by Cytochrome P450

i-Oxidation of the carbon atom α to the nitrogen:
oxidation reaction leading to the elimination of alkyl groups (especially methyl groups). oxidative N-dealkylation.

carbinolamine

• α-carbon hydroxylation gives unstable carbinolamine intermediate which undergoes spontaneous heterolytic cleavage of the C-N bond giving secondary amine + carbonyl moiety.

I-Tertiary alphatic amines:

• rules which govern the N-dealkylation reactions:

1-small alkyl groups e.g. methyl, ethyl and isopropyl are removed rapidly

2- α-carbon involved has to be attached to a hydrogen atom.
Exception N-dealkylation of the t-butyl group through carbinolamine intermediate not possible since α-carbon hydroxylation cannot take place (no α H).

• Can take place indirectly e.g. t-butylnorchlorocyclizine is metabolized by the removal of the t-butyl gp giving norchlorcyclizine.

3-The removal of first alkyl gp from tertiary amines is faster than second alkyl gp.

4- In tertiary amines with different substituents smaller alkyl group is more rapidly removed.e.g. benzphetamine.

5- Bisdealkylation of tertiary amines will give primary aliphatic amine which will lead to further oxidation as shown later.
6-Alicyclic tertiary amines undergo oxidative N-dealkylation. e.g. meperidine .

7-carbon α to an alicyclic nitrogen will undergo hydroxylation giving lactam metabolite. e.g.nicotine (below).
8-Dealkylation of tertiary amines is faster than secondary.

b- Oxidation of the nitrogen gives N-oxide which may undergo reduction by reductase to give tertiary amine again.

• N-oxide metabolite may possess pharmacological activity. e.g. imipramine oxidized to active N-oxide.


• N- oxidation is a minor metabolic pathway.
• Dealkylation more predominant.

II- Secondary aliphatic and alicyclic amines:

• The secondary amine may be parent drug or metabolite which will undergo metabolism by
  a- oxidation of the carbon α to the nitrogen giving.

i-N-dealkylation through carbinolamine intermediate giving primary amine metabolite.

propranolol..................Crbinolamine..........primary.........ketone
β-adrinergic blocker..............................aliphatic amine ..metabolite

ii-Oxidative deamination:

• similar to N-dealkylation.
• larger bulk of the molecule will be eliminated as a carbonyl metabolit.
• smaller bulk is removed as a small amine moiety.
• The mechanism is again through α-carbon hydroxylation giving carbinolamine intermediate leading to carbon-nitrogen cleavage and the formation of carbonyl + amine.

as shown below:
In case of a drug like Norketamine (below)

α-carbon has no H thus no α-carbon hydroxylation is possible thus deamination is not possible.

• Both reactions possible dealkylation first then deamination is more favourable.
• Secondary amines will undergo N-dealkylation before deamination.
• direct deamination of secondary amines takes place.
• propranolol has two α- carbon atoms which contain H (both subject to hydroxylation) leading to two possibilities :

A- N-Dealkylation followed by elimination of acetone moiety giving primary amine metabolite then deamination giving carbonyl metabolite.

OR
B-Direct dealkylation → elimination of isopropylamine → aldehyde metabolit.

Secondary alicyclic amines undergo α hydroxylation giving lactam metabolite e.g. phenmetrazine (shown below).
ii-Oxidation of the nitrogen atom:

• Results inseveral oxygenated products.

N-Hydroxylation will give the corresponding N-hydroxylamine metabolites which will undergo further oxidation (spontaneously or enzymatically) giving nitrone derivatives.

Example is N-benzylampheatmine sahown below).

III-Primary aliphatic amines:

• Parent drug or metabolite (Dealkylation of primary amine or bis dealkylation of secondary amine) will undergo
  a- Oxidation of the carbon α to the nitrogen leading to oxidative deamination (catalized by mixed function oxidases).

Endogenous primary amines e.g. dopamine, nor epinephrine → oxidative deamination
(monoamine oxidases (MAO)) inactivation.
b- Oxidation of the nitrogen atomleading to formation of N-hydroxyl amine (chemically unstable) which undergoes spontaneous or enzymatic oxidation giving nitroso and nitro derivatives.

Structural features of the α- substituent will determine which oxidation will take place that of the carbon or the nitrogen.
E.g. in phenteramine the Oxidation of Nitrogen inevitableas shown below:

• normally if α-carbon contains a H then either oxidation of N to give N oxide or Oxidation of C to give deamination as shown

Dealkylation is a more common pathway than N-oxidation in human
IIII-Oxidation of aromatic amines and heterocyclic nitrogen compounds

1-For tertiary aromatic amines: N-dealkylation and N-oxidation e.g. N,N-dimethylaniline.

2-Secondary aromatic amines:

1. N-dealkylation →primary amine or N-hydroxylation to give nitrone e.g. N-methyl-4-aminoazobenzene.

3- Primary aromatic amines:

• more common in drug
• Can be formed from metabolism of other compounds.
• Will be N-hydroxylated giving N-hydroxylamine which is further oxidized to the nitroso then nitro derivatives.
• Aromatic hydroxylamine.
• Nitrogen atoms in aromatic heterocyclic moieties undergo N-oxidation (minor extent)